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A small-molecule degrader of TET3 as treatment for anorexia nervosa in an animal model.

ABSTRACT: Anorexia nervosa (AN) is a psychiatric illness with the highest mortality. Current treatment options have been limited to psychotherapy and nutritional support, with low efficacy and high relapse rates. Hypothalamic AgRP (agouti-related peptide) neurons that coexpress AGRP and neuropeptide Y (NPY) play a critical role in driving feeding while also modulating other complex behaviors. We have previously reported that genetic ablation of Tet3, which encodes a member of the TET family dioxygenases, specifically in AgRP neurons in mice, activates these neurons and increases the expression of AGRP, NPY, and the vesicular GABA transporter (VGAT), leading to hyperphagia and anxiolytic effects. Bobcat339 is a synthetic small molecule predicted to bind to the catalytic pockets of TET proteins. Here, we report that Bobcat339 is effective in mitigating AN and anxiety/depressive-like behaviors using a well-established mouse model of activity-based anorexia (ABA). We show that treating mice with Bobcat339 decreases TET3 expression in AgRP neurons and activates these neurons leading to increased feeding, decreased compulsive running, and diminished lethality in the ABA model. Mechanistically, Bobcat339 induces TET3 protein degradation while simultaneously stimulating the expression of AGRP, NPY, and VGAT in a TET3-dependent manner both in mouse and human neuronal cells, demonstrating a conserved, previously unsuspected mode of action of Bobcat339. Our findings suggest that Bobcat339 may potentially be a therapeutic for anorexia nervosa and stress-related disorders.

SUBMITTER: Lv H

PROVIDER: S-EPMC10120042 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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A small-molecule degrader of TET3 as treatment for anorexia nervosa in an animal model.

Lv Haining H Catarino Jonatas J Li Da D Liu Beibei B Gao Xiao-Bing XB Horvath Tamas L TL Huang Yingqun Y

Proceedings of the National Academy of Sciences of the United States of America 20230410 16

Anorexia nervosa (AN) is a psychiatric illness with the highest mortality. Current treatment options have been limited to psychotherapy and nutritional support, with low efficacy and high relapse rates. Hypothalamic AgRP (agouti-related peptide) neurons that coexpress AGRP and neuropeptide Y (NPY) play a critical role in driving feeding while also modulating other complex behaviors. We have previously reported that genetic ablation of <i>Tet3</i>, which encodes a member of the TET family dioxyge ...[more]

PMID: 37036983

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Project description:ObjectiveLittle is known about how individuals with atypical anorexia nervosa (AN) respond to eating disorder (ED) treatment in a partial hospitalization program (PHP), nor how certain factors such as trauma, childhood abuse, psychiatric comorbidity, and suicidal thoughts and behaviors might contribute to poor treatment outcomes. Thus, the current study (1) compares prevalence of these factors between individuals with AN and atypical AN upon admission to an ED PHP, (2) compares PHP treatment response between groups, and (3) investigates whether experiencing these factors impacts treatment outcomes.MethodWe conducted a retrospective chart review of young adults admitted to a PHP with AN (n = 95) and atypical AN (n = 59). Histories of psychiatric comorbidities and adverse childhood experiences were obtained from initial psychiatric evaluations. ED symptoms were assessed at intake and discharge with the Eating Disorder Examination-Questionnaire (EDE-Q).ResultsNo significant differences were found at intake in ED symptom severity or prevalence of lifetime trauma, childhood abuse, number of psychiatric diagnoses, or suicidal thoughts and behavior. Symptomatology at discharge also did not differ between groups. Emotional abuse was significantly related to discharge shape and weight overvaluation. No other intake characteristics were significantly related to discharge symptomatology.DiscussionTo our knowledge, this is the first study to compare the prevalence of comorbidities for both AN and atypical AN, as well as differential treatment outcomes for these individuals in a PHP. Results add to growing literature suggesting that, other than weight, AN and atypical AN have few properties that reliably distinguish them from one another.Public significanceThis study adds to a growing body of literature that raises questions about whether anorexia nervosa (AN) and atypical AN are truly different diagnoses. Our findings suggest these two groups present to treatment in a partial hospitalization program (PHP) with similar ED symptoms, as well as prevalence of lifetime trauma, childhood abuse, suicidal thoughts and behavior, and number of psychiatric comorbidities, and demonstrate similar treatment trajectories in PHP.

Dataset Information

A small-molecule degrader of TET3 as treatment for anorexia nervosa in an animal model.

Publications

A small-molecule degrader of TET3 as treatment for anorexia nervosa in an animal model.

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